No abstract

Rodero et al. report the direct quantification of IFNα protein in monogenic interferonopathies, autoimmunity, and infectious disease states, made possible by the combination of digital ELISA and high-affinity autoantibodies isolated from APECED patients, revealing differential levels and cellular sources dependent on underlying pathology.

Migraine affects over a billion individuals worldwide but its genetic underpinning remains largely unknown. Here, we performed a genome-wide association study of 102,084 migraine cases and 771,257 controls and identified 123 loci, of which 86 are previously unknown. These loci provide an opportunity to evaluate shared and distinct genetic components in the two main migraine subtypes: migraine with aura and migraine without aura. Stratification of the risk loci using 29,679 cases with subtype information indicated three risk variants that seem specific for migraine with aura (in HMOX2, CACNA1A and MPPED2), two that seem specific for migraine without aura (near SPINK2 and near FECH) and nine that increase susceptibility for migraine regardless of subtype. The new risk loci include genes encoding recent migraine-specific drug targets, namely calcitonin gene-related peptide (CALCA/CALCB) and serotonin 1F receptor (HTR1F). Overall, genomic annotations among migraine-associated variants were enriched in both vascular and central nervous system tissue/cell types, supporting unequivocally that neurovascular mechanisms underlie migraine pathophysiology.

Cerebroretinal vasculopathy, hereditary vascular retinopathy, and hereditary endotheliopathy, retinopathy, nephropathy and stroke are neurovascular syndromes initially described as distinct entities. Recently they were shown to be one disease caused by C-terminal frame-shift mutations in TREX1, which was termed 'retinal vasculopathy with cerebral leukodystrophy'. Here we defined the genetic and clinicopathologic spectrum of this clinically and pathophysiologically poorly characterized and frequently misdiagnosed fatal neurovascular disorder. We identified five different TREX1 mutations in 78 members from 11 unrelated families and by using a standardized study protocol we retrospectively reviewed and aggregated the associated clinical, neuroimaging, and pathology data. Findings were similar across mutations and families. Sixty-four mutation carriers had vascular retinopathy. Neuroimaging revealed (i) punctate, hyperintense, white matter lesions with or without nodular enhancement in 97% of them; (ii) rim-enhancing mass lesions in 84%; and (iii) calcifications in the white matter in 52%. Ninety per cent had clinical manifestations of brain disease, including focal neurological deficits (68%), migraine (59%), cognitive impairment (56%), psychiatric disturbances (42%), and seizures (17%). One mutation carrier had enhancing brain lesions and neurological features but unknown retinopathy status. Additional systemic features included liver disease (78%), anaemia (74%), nephropathy (61%), hypertension (60%), mild Raynaud's phenomenon (40%), and gastro-intestinal bleeding (27%). Mean (AE standard deviation) age at diagnosis was 42.9 AE 8.3 years and at death 53.1 AE 9.6 years. Pathological examination revealed systemic vasculopathy with luminal narrowing and multi-laminated basement membranes. The 13 mutation carriers without retinopathy or brain lesions were on average 8 years younger (mean age: 35.1 AE 10.6 years). Of them, 54% had mild Raynaud's phenomenon, 42% had migraine, and 23% had psychiatric disturbances. Retinal vasculopathy with cerebral leukodystrophy is an autosomal dominant systemic small-vessel disease due to specific TREX1 mutations and clinically primarily characterized by (i) visual impairment from vascular retinopathy; and (ii) neurological decline and premature death due to progressive enhancing cerebral white matter lesions. Impaired liver and kidney function, anaemia sometimes associated with gastrointestinal bleeding, hypertension, migraine, and Raynaud's phenomenon appear to be part of the clinical spectrum as well. Penetrance

Hemiplegic migraine (HM) is a rare subtype of migraine with aura, characterized by transient hemiparesis during attacks. Diagnosis is based on the International Classification of Headache Disorders criteria (ICHD-II). Two types of HM are recognized: familial (FHM) and sporadic hemiplegic migraine (SHM). HM is genetically heterogeneous. Three genes have been identified (CACNA1A, ATP1A2, and SCN1A) but more, so far unknown genes, are involved. Clinically, attacks of the 3 subtypes cannot be distinguished. The diagnosis can be confirmed but not ruled out by genetic testing, because in some HM patients other, not yet identified, genes are involved. The presence of additional symptoms (such as chronic ataxia or epilepsy) may increase the likelihood of identifying a mutation. Additional diagnostics like imaging, CSF analysis, or an EEG are mainly performed to exclude other causes of focal neurological symptoms associated with headache. Conventional cerebral angiography is contraindicated in HM because this may provoke an attack. Because HM is a rare condition, no clinical treatment trials are available in this specific subgroup of migraine patients. Thus, the treatment of HM is based on empirical data, personal experience of the treating neurologist, and involves a trial-and-error strategy. Acetaminophen and NSAIDs often are the first choice in acute treatment. Although controversial in HM, triptans can be prescribed when headaches are not relieved sufficiently with common analgesics. An effective treatment for the severe and often prolonged aura symptoms is more warranted, but currently no such acute treatment is available. Prophylactic treatment can be considered when attack frequency exceeds 2 attacks per month, or when severe attacks pose a great burden that requires reduction of severity and frequency. In no strictly preferred order, flunarizine, sodium valproate, lamotrigine, verapamil, and acetazolamide can be tried. While less evidence is available for prophylactic treatment with topiramate, candesartan, and pizotifen, these drugs can also be considered. The use of propranolol in HM is more controversial, but evidence of adverse effects is insufficient to contraindicate beta-blockers.